AUTACOIDS-1.ppt
- 1. AUTACOIDS PATRICK OTIM FOM GULU UNIVERSITY 11/10/2022 1
- 2. AUTACOIDS These are local hormones. I.e. they are produced and have action in the vicinity where they are produced. These include; 1. Histamine 2. Bradykinin & Kallidin 3. 5 Hydroxytryptamine (5HT) 4. Autacoids derived from membrane phospholipid a. Eicosanoids – Arachidonic acid • (PG, PGI, TXA2, LT) b. Modified phospholipids – PAF 11/10/2022 2
- 3. Intro..continuation Autacoids are released in conditions such as; •Sinus problems. • hay fever, • bronchial asthma • hives and eczema, •contact dermatitis • food allergies, and reactions to drugs . 11/10/2022 3
- 4. Synthesis • Decarboxylation of amino acid L-histidine catalyzed by pyridoxal Phosphate-dependent L- histidine decarboxylase. • Ingested from food or formed by bacteria in the GIT • Storage sites: • perivascular tissue – mast cell • circulation – basophil (bound to chondroitin Sulphate) • others – GIT, lungs, skin, heart, liver, neural tissue, reproductive mucosa, rapidly growing tissues and body fluids 11/10/2022 4
- 5. Functions: 1. Role in allergic responses – Ag + IgE (bound to mast cells & basophils);Preformed mediators,most important mechanism of release/controlled by H2 esp. in skin & blood 2. Release of other autacoids 3. Release by drugs (morphine, urase, amines), peptides, venoms & other agents 4. Release by urticarias 5. Gastric secretagogue 6. Neurotransmitter increased wakefulness, thermoregulation 11/10/2022 5
- 6. HISTAMINE; Action in humans • Stimulation of gastric secretion in the GIT via H2 receptors. • Smooth muscle contraction (ileum, bronchus, bronchioles, uterus) thru H1. Reduces air flow in the first phase of asthma. • SM of blood vessels are dilated , increased vascular permeability thru H1. • Increases heart rate and cardiac out put thru H2. • Injected intradermal, histamine cause triple reaction; reddening (increased blood flow), weal (direct action on bld vessels) and flare. • H3 are present in the presynaptic sites and inhibit the release of other neurotransmitters • Skin, causes itching thru stimulation of H1 receptors. • CNS; it is transmitter. • It mediates allergic reaction in Rhinitis and urticaria thru H1. 6 11/10/2022
- 7. Selected Actions of Histaminein Humans HIST receptor location effects H1 Brain, smooth muscle, endothelium & heart Vasodilation, fall in blood pressure, headache, SM contraction H2 Brain, smooth muscle, GIT, & heart, mast cell SM relaxation, acid & pepsin secretion, salivary secretion. H3 Brain, autonomic nerve ending, some endothelia Inhibit the release of norepinephrine & vasoconstriction. H4 Brain, bone marrow, peripheral leucocytes, lungs 11/10/2022 7
- 8. H1 RECEPTOR ANTAGONISTS Pharmacokinetics: • Well absorbed from GIT (oral) • Onset – 30 minutes, duration – 3 to 6 hours • Widely distributed • Biotransformed in the liver; microsomal enzyme inducer • Excretion – kidneys 11/10/2022 8
- 9. Adverse Effects: 1. CNS : sedation, agitation, nervousness, delirium, tremors, incoordination, hallucinations, & convulsions - common in first generation antihistamines 2. GIT : vomiting, diarrhea, anorexia, nausea, epigastric distress, constipation - dryness of mouth, throat & airway, urinary retention - first generation 3. Headache, faintness 4. Chest tightness, palpitations, hypotension 5. Visual disturbances 6. Hematological - leukopenia, agranulocytosis, HA 11/10/2022 9
- 10. Therapeutic Uses: 1. dermatitis 2. allergic rhinitis 3. motion sickness & emesis 4. Parkinson’s disease 5. Insomnia 6. Adverse reactions 11/10/2022 10
- 11. Class First Gen. Agents: 1. Ethanolamine Diphenylhydramine Carbinoxamine- maleate Clemastine fumarate Dimenhydrinate Significant antimuscarinic activity Sedation, somnolence Incidence of GI symptoms Effective in emesis & motion sickness 2.Ethylenediamin e/ Ethylamine Pyrilamine Mepyramine Pyranesamine Most specific H1 antagonist Anticholinergic activity Feeble CNS effects Somnolence GI s/s common 3. Alkylamine Chlorpheniramine Pheniramine Chlorphenamine Most potent Not so prone to develop drowsiness More suitable for older patients Sedation/CNS stimulation 4. Piperazine Chlorcyclizine Oldest member 11/10/2022 11
- 12. Structural Class Prototype Characteristics 5. Phenothiazine Promethazine Anticholinergic Prominent sedation Counters motion sickness primarily antiemetic Second Gen.Agents 1. Piperidine Terfenadine Astemizole Levocabastine Loratadine Highly selective for H1 receptor Non-sedating (-) anticholonergic action (-) pass BBB incidence of S/E 2. Alkylamine Acrivastine Rapid onset of action (30 mins) (-) anticholinergic effects Reduce both wheal & flare response Potential to penetrate BBB Skin allergy Allergic rhinitis 3. Piperazine Cetirizine ,hyrdrox izine pamoate, meclizine, Rhinitis, urticaria (-) pass BBB 11/10/2022 12
- 13. 2nd generation cont.. • D. Piperazines • 1. Hydroxyzine HCl/pamoate (long acting) • 2. Cyclizine HCl/lactate • 3. Meclizine HCl • 4. Chlorcyclizine • E. Phenothiazines • 1. Promethazine HCl 13 11/10/2022
- 14. H2 RECEPTOR ANTAGONISTS Pharmacodynamics: •Inhibit gastric acid secretion •(-) effect of gastric motility, emptying time, LES sphincter, pancreatic & mucous secretion 11/10/2022 14
- 15. Adverse Effects Cimetidine: headache, dizziness • constipation, diarrhea •skin rashes •alterations of hepatic function •CNS disturbances (elderly & impaired RF) •BM depression – rare •Serum prolactin elevation •Sexual dysfunction & gynecomastia Ranitidine: Serum prolactin elevation 11/10/2022 15
- 16. Drug Interactions: • Cimetidine inhibits cyto p-450 – accumulation of warfarin, phenytoin, theophylline, propanolol, diazepam & phenobarbital • Ranitidine – weak inhibitor • Nizatidine & famotidine – do not inhibit cyto P – 450 • Therapeutic Uses: Peptic acid disorders 11/10/2022 16
- 17. Vasoactive Peptides • Vasoconstrictors—angiotensin II,vasopressin, endothelins, neuropeptide Y • Vasodilators—bradykinin, natri-uretic peptides, vasoactive intestinal peptides, substance P, neurotensin and calcitonin gene-related peptide (CGRP) 11/10/2022 17
- 18. Pharmacologic Properties • CVS: - increase force and force contraction -vasoconstriction • Smooth Muscle: - Bronchoconstriction • GIT: Enhanced motility 11/10/2022 18
- 19. Functions • pain – excites primary sensory neurons & provokes release of substance P, neurokinin A & CGRP • inflammation - permeability in microcirculation • production of IL-1 & TNF - • respiratory disease 11/10/2022 19
- 20. Pharmacological Properties 1. CVS – potent vasodilator (10x more than histamine) • Stimulate histamine release 2. Kidney - renal blood flow 3. Others: • spermatogenesis & promotes sperm motility • dilatation of fetal pulmonary artery closure of ductus arteriosus constriction of umbilical vessels 11/10/2022 20
- 21. 5 HYDROXYTRYPTAMINE (5HT) 1, 2, &3. • Found in enterochromaffin cells (90%), platelets and CNS • Sources : tunicates, mollusks, anthropods, colenterates, fruits, nuts, wasps & scorpions. Examples include olasetron and ondansetron are 5HT3 receptor antagonist, cyproheptadine- 5HT1 antagonist,. Etc. 11/10/2022 21
- 22. Antagonists: 1. Clozapine: Reduce incidence of EPS High affinity for dopamine receptors Reduced negative symptoms of schizophrenia 2. Risperidone: D2 receptor blocker Reduced negative symptoms of schizophrenia Low incidence of EPS 11/10/2022 22
- 23. 1. Clozapine: • Reduce incidence of EPS • High affinity for dopamine receptors • Reduced negative symptoms of schizophrenia 2. Risperidone: • D2 receptor blocker • Reduced negative symptoms of schizophrenia • Low incidence of EPS 3. Methysergide: used for diarrhea & malabsorption in patients with carcinoid tumors 11/10/2022 23
- 24. Cyproheptadine: • H1 blocker • Weak anticholinergic and mild CNS depressant. • Used for skin allergies, cold urticaria • Counteract the sexual side effects of SSRI’s 11/10/2022 24
- 25. LIPID-DERIVED AUTOCOIDS Eicosanoids • Formed from arachidonic acid • They are generated from phospholipids on demand by phospholipase A2 • In human, the principle eicosanoids are; prostaglandins, leukotrenes, thromboxanes, and lipoxins. And they participate in chiefly in inflamation, mucous secretion, SM contraction,vasodilation, and thrombin formation. Its action is mediated by G proteins . 11/10/2022 25
- 26. Cycloxygenase PGG2 PGH2 PGG2 PGE2 PGF2 PGD2 TXA2 PGF1 TXB2 11/10/2022 26
- 28. Therapeutic Uses 1. PGE1 (Misoprostol) – suppress gastric ulceration 2. PGE1 – improve harvest and storage of platelets for therapeutic transfusion - improve blood flow & tissue oxygenation in neonates (ductus arteriosus – vasodilatation)(alprostadil) 3. PGE1 – treatment of impotence 4. PGI2 epoprostanol inhibit platelet aggregation in hemodylasis. Esp in patients whom heparin is contraindicated. 5. Open angle glaucoma. Lantanoprost eye drop. 11/10/2022 28
- 29. PLATELETACTIVATING FACTOR (PAF) Platelet-activating factor, also variously termed PAF-acether and AGEPC (acetyl-glyceryl-ether-phosphorylcholine), is a biologically active lipid that can produce effects at exceedingly low concentrat. The name is somewhat misleading, because PAF has actions on a variety of different target cells, Synthesized by platelets, neutophils,monocytes, mast cells, eosinophils, renal mesangial cells, renal medullary cells & vascular endothelial cells 11/10/2022 29
- 30. Cont.. • It is believed to be an important mediator in both acute and chronic allergic and inflammatory phenomena. PAF is biosynthesised from acyl-PAF in a two-step process . The action of PLA2 on acyl-PAF produces lyso-PAF, which is then acetylated to give PAF. PAF, in turn, can be deacetylated to the inactive lyso-PAF 30 11/10/2022
- 31. Pharmacological Properties A. CVS: Potent vasodilator vascular permeability 1000x more than histamine/bradykinin B. Leukocyte: Chemotaxis C. Smooth Muscle: • Contraction • Airway resistance & responsiveness to other bronchoconstrictors D. Stomach • Potent ulcerogen 11/10/2022 31
- 32. Mast cell stabilizer • Sodium cromoglycate. The compound stabilizes the cell membrane of mast cell and inhibit the release of its content. • Indication include; food allergy, asthma, allergic conjunctivitis, allergic rhinitis. • Dose 200mg 4 times daily before meals. May be increased if necessary after 2-3 weeks to max of 40mg/kg daily and then reduced according to response. • Side effects; occasional nausea , rashes, and joint pain. 32 11/10/2022